| Autor: |
Aigrot, Marie‐Stéphane, Barthelemy, Clara, Moyon, Sarah, Dufayet‐Chaffaud, Gaelle, Izagirre‐Urizar, Leire, Gillet‐Legrand, Beatrix, Tada, Satoru, Bayón‐Cordero, Laura, Chara, Juan‐Carlos, Matute, Carlos, Cartier, Nathalie, Lubetzki, Catherine, Tepavčević, Vanja |
| Zdroj: |
EMBO Molecular Medicine; 8/8/2022, Vol. 14 Issue 8, p1-17, 17p |
| Abstrakt: |
Preventing neurodegeneration‐associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents axonal degeneration, promoting this process in patients might enhance neuroprotection. In demyelinating mouse lesions, local overexpression of semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases remyelination. However, molecular targeting to MS lesions is a challenge. A clinically relevant paradigm for delivering Sema3F to demyelinating lesions could be to use blood‐derived macrophages as vehicles. Thus, we chose transplantation of genetically modified hematopoietic stem cells (HSCs) as means of obtaining chimeric mice with circulating Sema3F‐overexpressing monocytes. We demonstrated that Sema3F‐transduced HSCs stimulate OPC migration in a neuropilin 2 (Nrp2, Sema3F receptor)‐dependent fashion, which was conserved in middle‐aged OPCs. While demyelinating lesions induced in mice with Sema3F‐expressing blood cells showed no changes in inflammation and OPC survival, OPC recruitment was enhanced which accelerated the onset of remyelination. Our results provide a proof of concept that blood cells, particularly monocytes/macrophages, can be used to deliver pro‐remyelinating agents "at the right time and place," suggesting novel means for remyelination‐promoting strategies in MS. Synopsis: While several pro‐remyelinating molecules have been identified, targeting these to demyelinated MS lesions, disseminated in the CNS, is a major challenge. This study shows that blood–macrophages can be used as efficient molecular deliverers to demyelinating CNS lesions to increase remyelination. Transplanted hematopoietic stem cells give rise to macrophages that infiltrate CNS lesions shortly after demyelination.HSCs genetically modified to overexpress Sema3F secrete Sema3F that attracts both young and middle‐aged OPCs in vitro.Lesions in chimeric mice with Sema3F‐overexpressing hematopoietic cells show increased OPC recruitment, followed by accelerated generation of new oligodendrocytes and remyelination. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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